Locoregional CAR ‐T Therapy for HCC : Potential and Pathways Forward

We sincerely thank Mr. Wang and Dr. Chen for their insightful feedback on our study [1, 2]. We are encouraged by their recognition of the potential of locoregional delivery of anti-GPC3 CAR-T cells and appreciate their suggestions for further optimisation and clinical translation. Below, we respond to and supplement the key points raised in their letter. First, we agree that hepatic artery infusion (HAI)-specific delivery parameters should be further investigated in the future. We acknowledge the distinction between portal-vein injection in our preclinical mouse models and HAI in clinical settings. The bolus portal-vein injection we employed does not fully replicate the continuous or intermittent infusion used in HAI. We agree that further preclinical studies are warranted to mimic clinical HAI and assess the impact of parameters such as infusion rate and frequency. Such studies could provide valuable insights into whether prolonged local exposure affects CAR-T cell persistence and functionality. Currently, technical limitations in small animal models hinder the implementation of sustained infusion or repeated injections at short intervals via the portal vein. However, advancements in catheterisation and infusion pump technologies for murine models could help bridge this gap [3]. Second, we appreciate the authors' comments regarding the absence of cirrhosis and portal hypertension in our immunodeficient mouse models. These comorbidities are indeed common in HCC patients. On one hand, HAI-specific bleeding risks are minimal despite venous complications in cirrhosis. Prior clinical evidence robustly supports the safety of HAI in cirrhotic patients with portal hypertension and altered vascular flow dynamics. Increased risk of cirrhosis-associated bleeding mainly results from portal venous hypertension (e.g., variceal rupture or portal hypertensive gastropathy) and coagulopathy, rather than from arterial interventions such as HAI [4]. On the other hand, the impact of liver cirrhosis on CAR-T cell trafficking remains largely uninvestigated. Given the evidence that cirrhosis can alter sinusoidal architecture, endothelial interactions, chemokine gradients, and immune composition in local microenvironment, further preclinical research is needed to investigate its influence on CAR-T infiltration and functionality using clinically relevant models, such as humanised patient-derived xenografts (PDX) or immunocompetent mice with induced cirrhosis. This research could provide valuable insights for evaluating the potential benefits of locoregional CAR-T delivery in real-world applications. Meanwhile, we fully agree that stratifying patients by liver function and tumour burden in future clinical trials will be critical for addressing this question and the potential of tailoring locoregional CAR-T therapy to specific subgroups. Last, we thank the authors for highlighting the dual role of IFN-γ in CAR-T therapy, which is indeed a complex and critical aspect that warrants further investigation. High levels of IFN-γ can have both beneficial and detrimental effects, depending on the intensity, duration and inflammatory context. While they can evoke cytotoxic programs in immune cells, sustained signalling may expedite exhaustion. As noted, the absence of cross-reactivity between human IFN-γ and mouse immune cells limits our models in recapitulating the influence of high IFN-γ on host immunity and tumour microenvironment, which may lead to severe cytokine release syndrome (CRS), activation of endogenous macrophages and other myeloid cells, and immune effector cell-associated neurotoxicity syndrome (ICANS). Future studies using humanised PDX models or immunocompetent mice will be essential for elucidating the interplay between high IFN-γ and host immunity during locoregional CAR-T therapy and evaluating its effects on CAR-T functionality and treatment outcomes. Moreover, exploring strategies to modulate IFN-γ signalling, such as antibody blockade or combination with immune checkpoint inhibitors [5], may further optimise the therapeutic efficacy of locoregional CAR-T therapy. Collectively, we greatly appreciate the thoughtful critiques and recommendations provided by Mr. Wang and Dr. Chen. Their suggestions are valuable for further refining the locoregional delivery strategy and exploring its clinical applicability. By addressing the highlighted gaps—such as replicating clinical HAI parameters, incorporating models with cirrhosis and investigating the contextual role of IFN-γ—research can better assess and confirm the translational potential of anti-GPC3 CAR-T therapy for HCC. We thank the authors for their recognition and valuable feedback on our work. We hope this exchange fosters future collaborations and inspires further innovation in CAR-T therapy for HCC. Jue Wang: manuscript draft. Bo Feng and Jiale Qiu: draft review and editing. This work was supported by funds provided by the Research Grants Council of Hong Kong (14115520, 14106024 to B.F.), and in part by the Innovation and Technology Fund (ITF) (MHP/110/23 to B.F.) and the Health@InnoHK Program launched by the Innovation Technology Commission of the Hong Kong SAR, China. J.Q. received a graduate studentship from the Chinese University of Hong Kong. The authors declare no conflicts of interest. This article is linked to Wang and Chen paper. To view this article, visit https://doi.org/10.1111/liv.70484. The authors have nothing to report.